Contemporary outcomes in IDH-mutated acute myeloid leukemia: The impact of co-occurring NPM1 mutations and venetoclax-based treatment

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1(mut) AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2(mut) (N = 229) or IDHwt/NPM1(mut) AML (N = 208). In multivariate analysis, patients with IDH2(mut) (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDHwt/NPM1(mut) (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1(mut) AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1(mut) with similar OS observed between IDH1(mut)/NPM1(wt), IDH2(mut)/NPM1(wt), and IDHwt/NPM1(mut) AML. With regards to the influence of IDHmut/NPM1(mut) cases, IC improved survival in IDH2(mut)/NPM1(mut) versus IDH2(mut)/NPM1(wt) AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1(mut)/NPM1(mut) versus IDH1(mut)/NPM1(wt) AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1(mut) versus IDH2(mut) or NPM1(mut) AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1(mut) AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.